Clinical Trials Register

Summary
EudraCT Number:	2010-019181-91
Sponsor's Protocol Code Number:	EAURF2008-01
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2013-05-21
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - PEI

A.2

EudraCT number

2010-019181-91

A.3

Full title of the trial

Treatment of High Grade Non-Muscle Invasive Urothelial Carcinoma of the Bladder by Standard Number and Dose of Intravesical BCG Instillations Versus Reduced Number of Intravesical Instillations with Standard Dose of BCG.
A European Association of Urology Research Foundation Randomised Phase III Clinical Trial - NIMBUS.

Behandlung des high-grade nicht-muskelinvasiven Urothelkarzinoms der Harnblase mit der Standard-Anzahl und Dosierung intravesikaler BCG-Instillationen versus eine reduzierte Anzahl intravesikaler BCG-Instillationen in der Standarddosierung: Eine European Association of Urology Research Foundation randomisierte Phase 3 Studie - NIMBUS

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Standard number and dose intravesical instillation therapy with BCG versus Reduced number and standard dose intravesical instillation therapy with BCG in patients with high grade non-muscle invasive urinary bladder carcinoma.

Standard Anzahl und Dosierung intravesikaler BCG-Instillationen im Vergleich zu einer reduzierten Anzahl von intravesikalen BCG-Instillationen mit Standarddosierung bei Patienten mit einem hochgradigen nicht-muskelinvasiven Harnblasenkarzinom.

A.3.2

Name or abbreviated title of the trial where available

Standard vs Reduced Frequency BCG instillation therapy

Standard im Vergleich zur reduzierter Frequenz von BCG-Instillationen

A.4.1

Sponsor's protocol code number

EAURF2008-01

A.5.4

Other Identifiers

Name:	Arbeitsgemeinschaft für Urologische Onkologie	Number:	AB37/10
Name:	Nederlands Trial Register	Number:	NTR4011
Name:	Deutsches Register Klinischer Studien	Number:	DRKS00005651

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	EAU Foundation for Urological Research
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	EAU Foundation for Urological Research
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	Deutsche Krebshilfe
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	EAU Foundation for Urological Research
B.5.2	Functional name of contact point	Project Manager
B.5.3	Address:
B.5.3.1	Street Address	Mr. E.N. van Kleffensstraat 5
B.5.3.2	Town/ city	Arnhem
B.5.3.3	Post code	6842 CV
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31263890677
B.5.5	Fax number	+31263890679
B.5.6	E-mail	researchfoundation@uroweb.org

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	BCG -medac
D.2.1.1.2	Name of the Marketing Authorisation holder	Medac
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	BCG Vaccine for intravesical instillation
D.3.4	Pharmaceutical form	Intravesical solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravesical use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	The IMP used for the standard arm is BCG vaccine which is payed by the insurances because it is the standard therapy. For this reduced frequency study arm, Medac is the sponsor for the BCG-Medac vaccine to be used in the reduced frequency study arm.
D.2.1.1.2	Name of the Marketing Authorisation holder	Medac
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	BCG Vaccine for intravesical instillation
D.3.4	Pharmaceutical form	Intravesical solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravesical use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	Yes
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Non muscle invasive bladder cancer after transurethral resection of the Bladder Tumor (TURT).

Nicht-muskelinvasives Harnblasenkarzinom nach operativer Entfernung (durch die Harnröhre) der(s) Tumor(s)en(TUR-Blase).

E.1.1.1

Medical condition in easily understood language

Non muscle invasive bladder cancer after transurethral resection of the Bladder Tumor (TURT).

Nicht-muskelinvasives Harnblasenkarzinom nach operativer Entfernung des Tumors durch die Harnröhre (TUR-Blase).

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10005003
E.1.2	Term	Bladder cancer
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this study is to identify if reduced number of BCG instillations are not inferior to standard number and dose intravesical BCG treatment in patients with high grade NMIBC. The primary endpoint for inferiority analysis is time to first recurrence.

Es ist das primäre Ziel der Studie zu zeigen, dass ein Schema mit reduzierter Anzahl BCG-Instillationen gegenüber dem Standard-Regime beim high risk nicht-muskelinvasiven Urothelkarzinom der Blase nicht unterlegen ist. Der primäre Studienendpunkt ist die Zeit bis zum ersten Rezidiv.

E.2.2

Secondary objectives of the trial

The secondary objectives are to identify if number and grade of recurrent tumors, rate of progression to a higher stage (T2 or higher) of the disease and safety, specifically the presence of treatment related toxicity > grade 2 differ between the two study arms.

Sekundäre Ziele der Studie sind zu zeigen ob Anzahl und Differenzierungsgrad der Tumorrezidive, die Rate an Progression zu einem höheren Tumorstadium (T2a oder höher) und die Sicherheit, insbesondere das Auftreten von behandlungsassoziierten Toxizitäten > Grad 2 sich unterscheiden zwischen den zwei Studienarmen.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

(1)Prospective evaluation of the influence of fluid restrictions before BCG instillation and technique of BCG instillation on side-effects and efficacy of treatment.
Patients with fluid restriction will be compared with patients without fluid restriction and patients with rotation during the instillation procedure will be compared with patients without rotation with respect to side effects and efficacy.
(2) Prospective evaluation of urinary cytokine levels in patients treated with reduced number of BCG intravesical instillations compared to standard BCG treatment.
One spot urine sample will be collected from each patient prior to each instillationa and 4 to 8 hr after each instillation both during the induction and maintenance period. Levels of IL-2, IL-4, IL10 and IFN-gamma will be determined in urine with commercially available, enzyme-linked immunosorbent assays.
(3) Validation of predictive genetic markers for BCG response.
From blood samples of trial participants who gave their informed consent for this substudy germline DNA will be isolated.
Single-SNP Centaurus assays (or a custom made chip) will be used to genotype genetic polymorphisms. SNP genotypes will be tested for association with recurrence- and progression-free survival after BCG treatment among the overall group of trial participants.

(1)Zukünftige Bewertung des Einflusses von Flüssigkeitsbeschränkungen vor BCG-Instillation und der Technik von BCG-Instillation auf Nebenwirkungen und der Wirksamkeit der Behandlung.
Patienten mit Flüssigkeitsbeschränkung werden mit Patienten ohne Flüssigkeitsbeschränkung verglichen und Patienten mit Rotation während des Intsillationsverfahrens werden mit Patienten ohne Rotation in Bezug auf Nebenwirkungen und Wirksamkeit verglichen.
(2) Zukünftige Bewertung der Urin-Zytokin-Konzentration in Patienten mit einer reduzierten Anzahl BCG-Instillationen im Vergleich zur Standardbehandlung. Eine Urinprobe wir vor der BCG-Instilation und eine Probe 4 bis 8 Stunden nach jeder Instillation gesammelt.Die Konzentration von IL-2, IL-4, IL-10 und IFN-gamma werden in den Proben mitteils Enzyme-linked immunosorbent Assay (ELISA) bestimmt.
(3)Validierung prädiktiver genetischer Marker für die Reaktion auf BCG. Aus den Blutproben der Patienten, die für die Teilnahme an der Substudie eingewilligt haben, erfolgt die DNA Isolation.Die Genotypisierung erfolgt mittels Single-SNP-Centaurus Assay. Die Genotypen der Einzelnukleotid-Polymorphismen werden auf den Zusammenhangs mit dem Rezidiv - und progressionsfreiem Überleben nach der BCG-Behandlung bei allen Studienteilnehmern untersucht.

E.3

Principal inclusion criteria

1. Presence of high grade (Ta-T1) urothelial papillary carcinoma of the bladder with or without CIS
1.1. Tumors can be primary or recurrent
1.2. Tumors can be single or multiple
2a. In case of a Ta high grade tumor in the initial resection, a re-TUR can be performed at the discretion of the investigator. Initial resection or re-TUR must include the deep resection or cold cup biopsy (deep enough to obtain muscle tisssue) of the (initial) tumor site(s)
2b. In case of a T1 high grade tumor in the initial resection, a Re-TUR should be performed at weeks 4-8 after initial resection, which must include the deep resection or cold cup biopsy (deep enough to obtain muscle tisssue) of the initial tumor site(s)
3. Re-re-TUR should be performed at weeks 4-8 after re-TUR in case of histological detection of T1 low/high grade tumor in the re-TUR, which must include the deep resection or cold cup biopsy (deep enough to obtain muscle tisssue) of the initial tumor site(s)
4. Histopathologically confirmed absence of T1 low/high grade tumor(s) in the re-TUR specimen and/or re-re-TUR specimen
5. All visible papillary tumors must be completely resected
6. If the patient is male, he must use a condom during sexual intercourse during the first week after BCG treatment. If the patient is female, and of childbearing potential, she must practice adequate contraception for 30 days prior to administration of study treatment, have a negative pregnancy test and continue such precautions during all study treatment period and for 3 months after the last BCG treatment.
7. Signed and dated informed consent form.
8. Patient is clinically fit enough to receive BCG bladder instillations.

E.4

Principal exclusion criteria

1. Any previous intravesical BCG therapy
2. Presence of primary CIS only.
3. Presence of histopathologically proven muscle invasive urothelial carcinoma of the bladder at first or (re-)re-TUR surgical specimens
4. Presence of any tumors in upper urinary tract or in the prostatic urethra at any time
5. Presence of any other histological type of resected tumor other than urothelial carcinoma on the first or second resection
6. Presence of another malignancy within 5 years except for basal cell carcinoma of the skin or localised prostate cancer in active surveillance
7. Presence of pregnancy or lactation
8. Presence of active tuberculosis, any form of immunodeficiency (eg HIV + serology, transplant recipients) and/or any other contraindication of BCG therapy
9. Patients who have received any systemic cytostatic agents or multi-instillation intravesical chemotherapy in the 3 months prior to randomisation. Early postoperative (within 6 hours of resection) single dose chemotherapy is allowed after the first resection. However, it should not be given after (re-)re-TUR if the patient is considered eligible for this study.
10. Patients with uncontrollable UTI

E.5 End points

E.5.1

Primary end point(s)

Time to first recurrence.

Zeit bis zum ersten Rezidiv.

E.5.1.1

Timepoint(s) of evaluation of this end point

Timepoint after randomisation at which the date of first recurrence of the disease occurs up to a maximum of 5 years from the first administration of BCG Vaccine for intravesical instillation.

Zeitpunkt nach der Randomisierung, zu dem nach Verabreichung der ersten BCG-Instillationstherapie bis zu einem Maximum von 5 Jahren nach erster Verabreichung zum ersten Mal ein Rezidiv der Erkrankung auftritt.

E.5.2

Secondary end point(s)

Number and grade of recurrent tumors.
Rate of progression to a higher stage (T2 or higher).
Incidence and severity of side effects, specifically the presence of treatment related toxicity > Grade 2.

Anzahl und Differenzierungsgrad der Rezidive.
Progressionsrate zu höherem Stadium (T2 oder höher).
Inzidenz und Schwere von Nebenwirkungen, insbesondere das Auftreten von behandlungsassoziierten Toxizitäten > Grad 2.

E.5.2.1

Timepoint(s) of evaluation of this end point

Timepoint after randomisation at which the date of first recurrence of the disease occurs up to a maximum of 5 years from the first administration of BCG Vaccine for intravesical instillation.
This timepoint will also be used for evaluation of the the secondary end points.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Standardzahl und Dosierung von BCG-Instillationen

Standard number and Dose of BCG instillations

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

Last visit of the last patient.

Letzter Besuch des letzten Patienten.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

450

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

550

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

330

F.4.2

For a multinational trial

F.4.2.1

In the EEA

824

F.4.2.2

In the whole clinical trial

824

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None. After recurrence, treatment will be performed according to the discretion of the treating physician.

Keine planmäßige Weiterbehandlung. Diese erfolgt wie üblich bei Rezidiv nach Ermessen des behandelnden Arztes.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2013-05-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-04-18

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2020-04-15

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